Simvastatin increases notch signaling activity and promotes arteriogenesis after stroke.
OBJECTIVE
Notch signaling activity regulates arteriogenesis. Presenilin 1 (PS1) mediates Notch signaling activity via cleavage of Notch, liberating Notch intracellular domain (NICD). We tested the hypothesis that simvastatin enhances arteriogenesis after stroke by increasing PS1 activation of the Notch signaling pathway.


METHODS
Rats were subjected to middle cerebral artery occlusion (MCAo) and treated with or without simvastatin (1 mg/kg) starting 24 hours after stroke and daily for 7 days; they were euthanized 14 days after stroke. Immunostaining, Western blot, and real-time polymerase chain reaction assays were performed.


RESULTS
Simvastatin significantly increased arterial diameter, density, and vascular smooth muscle cell proliferation, and upregulated PS1, Notch1, and NICD expression in the ischemic border tissue and in the cerebral arteries compared with MCAo control rats, respectively. However, simvastatin did not increase arteriogenesis, PS1, and NICD expression in sham control animals. To investigate the mechanisms of simvastatin-induced arteriogenesis, primary cerebral artery cultures were used. Rats were subjected to MCAo and treated with or without simvastatin daily for 7 days. The cerebral arteries derived from these stroke rats were cultured in matrigel and treated with or without a gamma40-secretase inhibitor II, which blocks Notch signaling activity, inhibiting NICD production. Arterial cell migration was measured. simvastatin treatment significantly increased arterial cell migration compared to control MCAo artery, whereas inhibition of Notch signaling activity by the gamma40-secretase inhibitor II significantly attenuated simvastatin-induced arterial cell migration.


CONCLUSIONS
These data indicate that simvastatin increases arteriogenesis after stroke, and that simvastatin upregulation of PS1 expression and Notch signaling activity may facilitate an increase in arteriogenesis.
Zacharek
Alex
A
Neurology Research, E&R Building, Room #3091, Henry Ford Hospital, 2799 West Grand Boulevard, Detroit, MI 48202, USA. jieli@neuro.hfh.edu
Chen
Jieli
J
Cui
Xu
X
Yang
Yuping
Y
Chopp
Michael
M
D000818:Animals; D001921:Brain / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology; D002536:Cerebral Arteries / Q000187:drug effects / Q000378:metabolism; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008833:Microcirculation / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000502:physiology; D018919:Neovascularization, Physiologic / Q000187:drug effects* / Q000502:physiology; D009924:Organ Culture Techniques; D053764:Presenilin-1 / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D051881:Receptor, Notch1 / Q000187:drug effects* / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use; D020521:Stroke / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D016896:Treatment Outcome; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology
D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C497763:Notch1 protein, rat; D053764:Presenilin-1; D051881:Receptor, Notch1; D019821:Simvastatin